Impact of Tigecycline on C. difficile Outcomes: Case Series and Propensity-Matched Retrospective Study

ABSTRACT This case series and propensity-matched cohort study on the use of tigecycline in Clostridioides difficile infection (CDI) evaluated the effect of tigecycline on 30-day mortality. Adjusted for ATLAS Score, hypotension, treatment time period, and serum lactate, tigecycline did not significantly improve 30-day mortality (odds ratio: 0.89; 95% confidence interval: 0.25–3.12; P = 0.853). A randomized controlled trial is needed to determine efficacy and safety of tigecycline in severe or refractory CDI.

and updated 2017 CDI management guidelines (15). Patients ,18 years, with . 5 prior recurrent episodes, or who did not receive active treatment (oral vancomycin, IV/oral metronidazole, or tigecycline) were excluded. Baseline clinical data, including laboratory measurements within 648 h of the positive PCR, and outcome data were gathered electronically from the UVA Clinical Data Warehouse. Modified Charlson Comorbidity Index was calculated using International Classification of Diseases coding data (16,17). ATLAS/Zar Scores were measured at diagnosis (18,19). Analyses were performed using statistical software R, version 4.0.4 (R Core Team, Vienna, Austria) with 'comorbidity,' 'MatchIt,' and 'gee' packages.
Baseline characteristics of each cohort are in Table 1. In the full cohort, tigecycline-treated patients had significantly higher pressor and antimotility agent use, lower albumin, and higher ATLAS and Zar Scores. A significantly higher proportion of tigecycline cases occurred after 2016. The propensity-matched cohort showed no significant differences in baseline characteristics.
The case series was manually compiled by investigator E. C. Phillips using REDCap data capture tools hosted at UVA (20,21). Cases were stratified into categories of nonsevere, severe, and fulminant infection based on current CDI management guideline criteria (15). Twenty-eight cases of tigecycline treatment were identified among 26 individuals. Seven out of twenty-eight (25%) cases were classified as nonsevere, 12/28 (43%) as severe, and 9/28 (32%) as fulminant infection. Tigecycline was given for an average 7.3 (range: 0.5-27.5; standard deviation: 6.1) days. In the nonsevere/severe groups, tigecycline was used primarily as salvage therapy (Table 2). Mortality was highest in the fulminant group, and recurrence rates were equivalent among surviving patients in the severe and fulminant groups. Tigecycline was used exclusively for CDI in 18/28 (64%) cases, CDI plus another infection in 4/28 (14%) cases, and primarily for another infection (examples include pneumonia, intrabdominal abscess, Enterobacter sepsis, and urinary tract infection) in 6/28 (21%) cases.
The primary outcome was 30-day all-cause mortality. Secondary outcomes were in-hospital mortality attributable to CDI, colectomy, or diverting ileostomy due to CDI, CDI recurrence,  (Table 3; odds ratio: 0.89; P = 0.853); however, this is limited by small case numbers.
Univariate and multivariable analyses of the secondary outcomes are shown in Table 4. Adjusted coefficients for tigecycline were significantly greater than zero for both total length of stay and length of stay following CDI diagnosis, indicating significantly longer lengths of stay with tigecycline. Colectomy/diverting ileostomy due to CDI, hospital mortality attributable to CDI, and subsequent recurrence were all not significantly associated with tigecycline in the univariate and multivariable analyses.
Although nonsignificant, the C. difficile-associated mortality in the later study period (2017-2021) was higher. This may be in part due to the aforementioned decision support tool, which led to 41% fewer tests and proportionally fewer cases with subclinical infection or colonization; therefore, the proportion of cases in the later period was not only higher, but also likely more severe (14).
There are several potential explanations for why tigecycline may not be effective adjunct therapy in CDI. Although not available clinically, oral tigecycline may be preferable to intravenous administration due to high protein binding in the bloodstream (22). Additionally, the FDA noted that most deaths from early clinical trials were related to progression of an under- a Initial therapy is defined as tigecycline use within 7 days from day 0: the earliest of the date of positive stool test, the start of directed antimicrobial therapy, or the start of tigecycline therapy. Salvage therapy is defined as tigecycline use after 7 days from day 0. An equals sign indicates that tigecycline was used as initial, salvage, or nondirected therapy in an equal number of cases. lying infection, perhaps owing to its bacteriostatic action and/or complex pharmacokinetics in the setting of bacteremic infections, which could be an underrecognized feature in severe CDI (https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication -fda-warns-increased-risk-death-iv-antibacterial-tygacil-tigecycline) (23). A strength of this study was its large pool of retrospective controls that allowed for robust 5:1 propensity matching; however, small numbers of cases represent a major limitation of the study. Additionally, as an observational study, there may have been bias associated with tigecycline treatment and severe outcomes that may not have been captured; for example, refractoriness of C. difficile-associated diarrhea and treatment response could not be reliably assessed using electronic medical record data. The process of clinical attribution for the secondary outcomes was not blinded to treatment status. Also, median time from CDI diagnosis to first tigecycline administration was 4 days (interquartile range: 6); these outcomes may have already occurred or begun to occur before tigecycline could have had an effect. Finally, tigecycline was utilized for other indications than CDI in several cases.
Tigecycline for adjunctive C. difficile treatment should be carefully weighed against delay in pursuing potentially life-saving aggressive measures such as surgical intervention. A randomized controlled trial is needed to better characterize the role, if any, of tigecycline in the treatment of severe, fulminant, and/or refractory C. difficile infection. ,0.001 a n (%) unless otherwise specified. P values for univariate analyses calculated using chi-square tests or independent-samples t tests (length of stay). P values in bold-faced type are considered to be significant. For results of multivariable logistic regression (colectomy/ileostomy, attributable mortality, recurrence) and linear regression (total length of stay, length of stay after CDI) with generalized estimating equation method (to adjust for within-subject correlation), all models were adjusted for ATLAS Score, hypotension, time period, and serum lactate. Hospital length of stay calculated between admission/discharge and length of stay after CDI calculated between CDI diagnosis and discharge. Length of stay regression coefficients represent the estimated differences (in days) for the tigecycline group compared with nontigecycline (coefficients significantly greater than zero interpreted as longer length of stay in tigecycline group). LOS, length of stay; CI, confidence interval; SD, standard deviation. b Generalized estimating equation method could not be applied to colectomy/diverting ileostomy due to low event numbers so ordinary multivariable logistic regression was used.